This competitive renewal from a multi-institutional group of investigators with longstanding interest in Rett syndrome (RTT) and RTT-related disorders continues a Rare Disease Clinical Research Center (RDCRC) within the Rare Diseases Clinical Research Network. This RDCRC will focus on three distinct disorders: RTT, MECP2 duplication disorder, and the RTT-related disorders including CDKL5, FOXG1, and individuals with MECP2 mutations but lacking clinical criteria for RTT. The near-term potential for meaningful therapies is tangible for RTT; the treatment potential for the other disorders is promising. Three overarching specific aims are proposed. 1) Perform longitudinal and neurobehavioral assessments on the core clinical features of each disorder: The on-going RTT NHS has provided critical data for organizing and advancing longitudinal studies. Substantial questions remain for RTT in terms of clinical variability not explainable solely by the specific mutations. Acquisition of similar data for the other disorders is equally important. 2) Perform robust biomarker and clinical outcome measures to identify biological factors that contribute to disease severity in each disorder: Providing critical guidance to effective and discriminant outcome measures is a crucial feature of any clinical trial and requires special consideration for these disorders. 3) Identify and characterize neurophysiological and neuroimaging correlates of disease severity in RTT and RTT-related disorders: Understanding alterations in specific volumetric measures, chemical composition, and neurophysiological measures such as EEG and Evoked Potentials are critical to advancing clinical knowledge. The RDCRC will maintain extensive training and pilot project programs cooperating directly with the respective CTSAs. The RDCRC will work with the Patient Advocacy Groups to ensure a full partnership and will rely principally on the Data Management and Coordinating Center for protocol management, data storage, a website portal, and biostatistical support. The UAB CCTS (CTSA) will fully cooperate with the RDCRC with pilot project development and additional biostatistical support. Website interfaces will be linked with the RDCRC, the DMCC, and the Patients Advocacy groups to ensure the widest reach of relevant information